NM_004525.3:c.248A>G

Variant names:

• chr2-169318824-T-C
• rs2229263
• NM_004525.3:c.248A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.248A>G​(p.Asn83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,613,762 control chromosomes in the GnomAD database, including 71,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8514 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63234 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.752
• Publications: 35 publications found

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.2864037E-4).
• BP6: Variant 2-169318824-T-C is Benign according to our data. Variant chr2-169318824-T-C is described in ClinVar as Benign. ClinVar VariationId is 129511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.248A>G	p.Asn83Ser	missense	Exon 3 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.248A>G	p.Asn83Ser	missense	Exon 3 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.248A>G	p.Asn83Ser	missense	Exon 3 of 23	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49520 AN: 151936 Hom.: 8498 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.272 AC: 68407 AN: 251368 AF XY: 0.270

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.280

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.290 AC: 423737 AN: 1461708 Hom.: 63234 Cov.: 40 AF XY: 0.287 AC XY: 208996 AN XY: 727162

African (AFR) AF: 0.452 AC: 15124 AN: 33474

American (AMR) AF: 0.171 AC: 7625 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8734 AN: 26134

East Asian (EAS) AF: 0.289 AC: 11455 AN: 39696

South Asian (SAS) AF: 0.198 AC: 17112 AN: 86256

European-Finnish (FIN) AF: 0.260 AC: 13865 AN: 53416

Middle Eastern (MID) AF: 0.278 AC: 1604 AN: 5766

European-Non Finnish (NFE) AF: 0.297 AC: 330503 AN: 1111878

Other (OTH) AF: 0.293 AC: 17715 AN: 60388

GnomAD4 genome AF: 0.326 AC: 49573 AN: 152054 Hom.: 8514 Cov.: 32 AF XY: 0.325 AC XY: 24126 AN XY: 74330

African (AFR) AF: 0.448 AC: 18581 AN: 41462

American (AMR) AF: 0.236 AC: 3605 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1431 AN: 5176

South Asian (SAS) AF: 0.204 AC: 984 AN: 4824

European-Finnish (FIN) AF: 0.263 AC: 2781 AN: 10578

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20073 AN: 67964

Other (OTH) AF: 0.317 AC: 669 AN: 2112

Alfa AF: 0.309 Hom.: 28534

Bravo AF: 0.329

TwinsUK AF: 0.286 AC: 1059

ALSPAC AF: 0.294 AC: 1133

ESP6500AA AF: 0.435 AC: 1915

ESP6500EA AF: 0.293 AC: 2524

ExAC AF: 0.278 AC: 33762

Asia WGS AF: 0.228 AC: 796 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.310

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.072
DANN	Benign	0.29
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.00093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.080	N
PhyloP100		-0.75
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.13
Sift	Benign	0.82	T
Sift4G	Benign	0.74	T
Polyphen		0.0030	B
Vest4		0.083
MPC		0.19
ClinPred		0.0000096	T
GERP RS		-6.3
Varity_R		0.042
gMVP		0.23
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229263; hg19: chr2-170175334; COSMIC: COSV55541386;